OBJECTIVESThe voltage-dependent L-type calcium channel α-subunit 1c (Cav1.2, CACNA1C) undergoes extensive mRNA splicing, leading to numerous isoforms with different functions. L-type calcium channel ...blockers are used in the treatment of hypertension and arrhythmias, but response varies between individuals. We have studied the interindividual variability in mRNA expression and splicing of CACNA1C, in 65 heart tissue samples, taken from heart transplant recipients.
METHODSSplice variants were measured quantitatively by polymerase chain reaction in 12 splicing loci of CACNA1C mRNA. To search for functional cis-acting polymorphisms, we determined allelic expression ratios for total CACNA1C mRNA and several splice variants using marker single nucleotide polymorphisms in exon 4 and exon 30.
RESULTSTotal CACNA1C mRNA levels varied ∼50-fold. Substantial splicing occurred in six loci generating two or more splice variants, some with known functional differences. Splice patterns varied broadly between individuals. Two heart tissues expressed predominantly the dihydropyridine-sensitive smooth muscle isoform of CACNA1C (containing exon 8), rather than the cardiac isoform (containing exon 8a). Lack of significant allelic expression imbalance, observed with total mRNA and several splice variants, argued against CACNA1C polymorphisms as a cause of variability. Taken together, highly variable splicing can cause profound phenotypic variations of CACNA1C function, potentially associated with disease susceptibility and response to L-type calcium channel blockers.
Ankyrins (ankyrin-R, -B, and -G) are adapter proteins linked with defects in metazoan physiology. Ankyrin-B (encoded by ANK2) loss-of-function mutations are directly associated with human ...cardiovascular phenotypes including sinus node disease, atrial fibrillation, ventricular tachycardia, and sudden cardiac death. Despite the link between ankyrin-B dysfunction and monogenic disease, there are no data linking ankyrin-B regulation with common forms of human heart failure. Here, we report that ankyrin-B levels are altered in both ischemic and non-ischemic human heart failure. Mechanistically, we demonstrate that cardiac ankyrin-B levels are tightly regulated downstream of reactive oxygen species, intracellular calcium, and the calcium-dependent protease calpain, all hallmarks of human myocardial injury and heart failure. Surprisingly, β(II)-spectrin, previously thought to mediate ankyrin-dependent modulation in the nervous system and heart, is not coordinately regulated with ankyrin-B or its downstream partners. Finally, our data implicate ankyrin-B expression as required for vertebrate myocardial protection as hearts deficient in ankyrin-B show increased cardiac damage and impaired function relative to wild-type mouse hearts following ischemia reperfusion. In summary, our findings provide the data of ankyrin-B regulation in human heart failure, provide insight into candidate pathways for ankyrin-B regulation in acquired human cardiovascular disease, and surprisingly, implicate ankyrin-B as a molecular component for cardioprotection following ischemia.
For trainees entering clinical practice, mentorship can be most helpful, and for those with an academic interest, mentorship is vital. A mentor can be a personal teacher, tutor, advisor, and coach. ...In addition to those pursuing academic advancement, similar issues also affect physicians entering a practice setting who are seeking comprehensive mentoring from their senior colleagues. The clinical trainee interested in pursuing a general clinical field or specialty can often achieve his/her goals with a personal faculty confidant or advisor. Here, Leier et al offer steps in choosing mentor.
Aims The objective of this study was to examine the burden of psychological distress among individuals with different forms of heart disease in a large representative sample of adults. Methods and ...results Data were obtained from the 2002 National Health Interview Survey, which is a large annual survey of the US non-institutionalized civilian population. Psychological distress was assessed with a standardized questionnaire (K6) and heart disease diagnoses were based on self-report. Among non-diseased individuals, the estimated prevalence of psychological distress was 2.8%, whereas the estimates were 10, 6.4, and 4.1% among those with congestive heart failure (CHF), myocardial infarction (MI), and coronary heart disease (CHD), respectively. Over 1 million individuals with one or more of these conditions are estimated to experience psychological distress. However, only 31–35% of the participants with heart disease and psychological distress have visited a mental health professional. The logistic regression model results indicate that MI (OR 2.0, 95% CI 1.4–3.0) and CHF (OR 3.1, 95% CI 1.8–5.1) are significantly associated with psychological distress. Conclusion These findings imply that psychological distress is a significant comorbidity of cardiovascular disease. Other investigations have demonstrated a link between psychological distress and morbidity and mortality. Taken together, these findings provide the impetus for future investigations that assess the role that a medical and mental health care professional intervention may have in altering these outcomes when targeted at this distress.
Abstract Objectives Objectives of this study were to examine the constructs of the Theory of Planned Behavior and determine how they predict Lebanese medical students’ behavioral intention to advise ...patients to quit smoking. Study design This was a cross-sectional study conducted among 191 medical students from six medical schools in Lebanon. Methods The instrument contained scales that measured attitudes toward the behavior, behavioral beliefs, subjective norms, and perceived behavioral control. Psychometric properties of the scale were examined. Item to total scale score correlations were determined and linear regression was conducted to predict the intention to advise smokers to quit. Results Respondents had a positive, but not very high, intention to deliver smoking cessation advice. Students reported a positive attitude toward advising patients to quit cigarette smoking and a strong belief in the physician’s obligations in smoking cessation advising. The majority reported lack of time to provide smoking cessation advice, insufficient knowledge of pharmacological aids, and the lack of openness of the patient to receive the advice. The attitude scale was the only variable that yielded a significant prediction of the intended behavior. Conclusions The construct of attitude toward the behavior appeared to be the most predictive of the intention to deliver advice to quit smoking among Lebanese medical students. Focusing training efforts on this construct could improve the rate of delivery of brief cessation counseling.
Indicated for treating hyperlipidemias and for the prevention of cardiovascular disease (CVD), statins rank among the most commonly prescribed drug classes. While statins are considered to be highly ...effective in preventing atherosclerotic events, a substantial portion of treated patients still progress to overt CVD. Genetic factors are thought to contribute substantially to treatment outcome. Several candidate genes have been associated with statin dose requirements and treatment outcomes, but a clinically relevant pharmacogenomics test to guide statin therapy has not yet emerged. Here we define basic pharmacogenomics terminology, present strong candidate genes (CETP, HMGCR, SLCO1B1, ABCB1, and CYP3A4/5), and discuss the challenges in developing much-needed statin pharmacogenomics biomarkers for predicting treatment outcomes.
The grant is from the National Institute of Allergy & Infectious Diseases, and its number is AI084898. (2013) Correction: Evidence for the Role of Epstein Barr Virus Infections in the Pathogenesis of ...Acute Coronary Events.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tobacco is the leading preventable cause of death worldwide. 1 Nearly 63% of men and 10% of women in Middle Eastern countries use tobacco. 2 In North Africa, approximately 19% of all adults smoke ...tobacco. 1 Public health efforts and the involvement of medical and health personnel have decreased smoking rates in most developed countries. 3 The WHO MPOWER package of policies and interventions recommended the involvement of physicians and other healthcare professionals in reducing the tobacco burden. 4 The package provides a reference model to implement tobacco control strategies that have been shown to reduce tobacco use. 4 Several studies have been conducted in Europe and the USA to investigate the proficiency of medical students in treating tobacco dependence. 5-10 Findings from two European medical schools indicated that teaching of smoking cessation methods is not a top priority in most medical curricula, and overall knowledge of long-term effectiveness of smoking cessation methods among students was poor. 8 In the USA, the results of a project conducted in 12 medical schools to assess and improve medical education showed that 36% of the courses included some tobacco information. 7 A recent web-based survey among the 4th year medical students in six New York City medical schools indicated that students had good knowledge on the harms of smoking, but required more integration of information on the benefits of smoking cessation and the treatment of tobacco dependence. 10 In medical schools of the Middle Eastern and North African (MENA) regions, there is a general lack of information on how tobacco dependence and treatment is incorporated into the curriculum.
Protein kinase A signaling has long been known to play an important role in cardiac function. Dysregulation of the protein kinase A system, caused by mutation of the protein kinase A regulatory ...subunit gene PRKAR1A, causes the inherited tumor syndrome Carney complex, which includes cardiac myxomas as one of its cardinal features. Mouse models of this genetic defect have been unsatisfactory because homozygote null animals die early in development and heterozygotes do not exhibit a cardiac phenotype.
To study the cardiac-specific effects resulting from complete loss of Prkar1a, we used cre-lox technology to generate mice lacking this protein specifically in cardiomyocytes. Conditional knockout mice died at day 11.5 to 12.5 of embryogenesis with thin-walled, dilated hearts. These hearts showed elevated protein kinase A activity and decreased cardiomyocyte proliferation before demise. Analysis of the expression of transcription factors required for cardiogenesis revealed downregulation of key cardiac transcription factors such as the serum response factor, Gata4, and Nkx2-5. Although heart wall thickness was reduced overall, specific areas exhibited morphological changes consistent with myxomatous degeneration in the walls of knockout hearts.
Loss of Prkar1a from the heart causes a failure of proper myocardial development with subsequent cardiac failure and embryonic demise. These changes appear to be due to suppression of cardiac-specific transcription by increased protein kinase A activity. These biochemical changes lead to myxoma-like changes, indicating that these mice may be a good model with which to study the formation of these tumors.
Abstract only Background: Approximately 3 million Americans have ill managed lipidemia due to statin intolerance (SI) or statin-associated myopathy (SAM). Atorvastatin and simvastatin are the most ...prescribed statins which are transported into the liver by SLCO1B1 and metabolized by cytochrome P450 (CYP) 3A4 and 3A5. CYP3A4*22 and CYP3A5*3 are two polymorphisms known to decrease their activity; thus, increasing the systemic daily exposure (AUC) and serum concentration (C max ) of unmetabolized statin. In Caucasian (CAU) populations the prevalence 5-7% CYP3A4*22 and 90% CYP3A5*3 and effect of these polymorphisms is well characterized but not in African American (AA) populations. We hypothesize that the prevalence of SI and SAM are correlated with CYP3A4/5 polymorphisms in AA populations. Methods: After IRB approval, saliva samples were collected from patients currently prescribed atorvastatin or simvastatin at The Ohio State University Medical for genotyping. SLCO1B1 status was assessed to control for its confounding effect. Participants with polymorphic results were contacted to complete 8 blood draws over 13hrs for pharmacokinetic analysis. Electronic medical records were utilized to collect demographic information, medical histories, risk factors, and concomitant medications. Results: Preliminary analysis of 502 participants (395 AA, 104 CAU, and 3 others) shows racially different polymorphic prevalence. Reduced activity of CYP3A4 was present in 5.8% CAU vs 0.51% AA. Notably, CYP3A5*3 is inactive in 73% and reduced in 20.3% of CAU compared to 41.7% and 40.7% respectively in AA. A statistically significant increase in SI in AA women vs CAU women (p=0.0032) was observed. In combined analysis, atorvastatin has reduced odds of intolerance compared to simvastatin (OR=0.463; p <0.05). However, the odds of SAM is higher in patients with no history of cardiovascular disease (OR=6.137; p <0.01) and those with chronic kidney disease (OR=1.269; p <0.05). Clinical significance: Considering, the CYP3A5 is fully active in 18.5% of the AA population compared to 6.8% CAU, the characterization of this metabolic enzyme is of clinical significance in minority populations to better manage lipidemia, assess the safety profile of current therapeutic doses, and reduce SAM.
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